The present invention relates to pharmaceutical compositions of a low-solubility drug and a high surface area substrate, wherein the drug and substrate are combined to form an adsorbate.
Low-solubility drugs often show poor bioavailability or irregular absorption, the degree of irregularity being affected by factors such as dose level, fed state of the patient, and form of the drug. Increasing the bioavailability of low-solubility drugs has been the subject of much research. Increasing bioavailability hinges on improving the concentration of the drug in solution to improve absorption.
It is well known that the amorphous form of a low-solubility drug that is capable of existing in either the crystalline or amorphous form may temporarily provide a greater aqueous concentration of drug relative to the equilibrium concentration obtained by dissolution of drug in a use environment. Such amorphous forms may consist of the amorphous drug alone, a dispersion of the drug in a matrix material, or the drug adsorbed onto a substrate. It is believed that such amorphous forms of the drug may dissolve more rapidly than the crystalline form, often dissolving faster than the drug can precipitate from solution. As a result, the amorphous form may temporarily provide a greater-than equilibrium concentration of drug.
While such amorphous forms may show initially enhanced concentration of the drug in a use environment, nevertheless the improved concentration is often short-lived. Typically, the initially enhanced drug concentration is only temporary and quickly returns to the lower equilibrium concentration.
One problem with using the amorphous form of a drug is that the solid drug may not be stable physically in the amorphous form. Often the crystalline form of the drug has a lower free energy, and thus over time, the amorphous drug will tend to crystallize. The rate of crystallization may be influenced by storage conditions, such as temperature and humidity, as well as the constituents of the composition.
D. Monkhouse, et al., Use of Adsorbents in Enhancement of Drug Dissolution I, J. Pharm. Sciences, Vol. 61, No. 9, p. 1430 (1972), disclose forming adsorbents by mixing a drug and water-insoluble adsorbent such as fumed silicon dioxide or silicic acid, adding a sufficient quantity of an organic solvent to dissolve the drug, and then evaporating the solvent by a stream of filtered air. The authors report improved drug dissolution rates.
Matsui, et al., U.S. Pat. No. 4,772,627, disclose a ground mixture of a poorly soluble crystalline drug and an adsorbent. The mixture of drug and adsorbent is ground to obtain amorphous drug. Enhanced drug dissolution and drug absorption is reported.
Denick, Jr. et al., U.S. Pat. No. 4,711,774, disclose an adsorbate of a drug and a complex magnesium aluminum silicate. The drug is dissolved in a solvent and added to magnesium aluminum silicate, and then dried. The adsorbate is used to mask the taste of bitter drugs.
Lovrecich, U.S. Pat. No. 5,449,521, discloses amorphous drug absorbed onto a support material. The support material may be crosslinked polymers, linear polymers, water soluble complexing agents, and porous inorganic materials. The drug and support material are co-ground in a mill with its grinding chamber saturated with the vapour of one or more solvents able to solubilize the drug. The resulting product is dried and sieved. The resulting compositions are reported to have a reduced heat of fusion, a reduced melting point, an increased dissolution rate and increased solubilization kinetices.
Accordingly, what is still desired is a composition comprising an amorphous drug form that is physically stable under typical storage conditions, and that may enhance the bioavailability of poorly soluble drugs. These needs and others that will become apparent to one of ordinary skill are met by the present invention, which is summarized and described in detail below.